The present invention concerns a method for long term prevention and/or treatment of dysglucaemia and/or for improved glycaemic control, for example the long term prevention of nocturnal and morning hypoglycaemia in diabetic patients, a composition for this purpose and a method for its production.
Dysglucaemia is an overall definition, which in the present description and claims is meant to comprise all irregularities in blood glucose level in humans, both healthy persons and persons with a diagnosed disease, irrespective of these irregularities being chronic or temporary, caused by a metabolic disorder, a disease or by physical exercise, bad nutritional habits, medical treatment such as surgery, and desired or undesired pharmaceutical or chemical influences, such as pharmaceutical treatments or substance abuse.
Diabetes mellitus is a complex disorder of the carbohydrate, fat, and protein metabolism that is primarily a result of a relative or complete lack of insulin secretion by the beta cells of the pancreas or of defects of the insulin receptors. The various forms of diabetes are divided in several categories, the two most frequent being juvenile-onset diabetes or Type I insulin-dependent diabetes mellitus (IDDM) and adult-onset diabetes or Type II non-insulin-dependent diabetes mellitus (NIDDM). Both diseases, even when correctly diagnosed and medicated, require life-long medication, good patient compliance, a careful diet and frequent medical observation to avoid potentially serious sequelae.
One problem, frequently encountered by patients suffering from diabetes, is the nocturnal drop in blood glucose levels, hypoglycaemia, in mild cases resulting in morning dizziness and/or nausea. Occasionally the blood glucose level sinks so low during the night, or early in the morning, that the state of hypoglycaemia becomes severe, leading to unconsciousness or convulsions. Importantly, severe hypoglycaemia is more likely to occur at night, when the patient is asleep, rather than during the day, when the patient can feel the onset of hypoglycaemia and prevent it by eating carbohydrates, e.g. a lump of sugar or specific glucose tablets, energy gels or bars, marketed for diabetic patients.
Moreover, both mild (a blood glucose level about 2.4-4.0 mmol/l) and severe (less than 2.4 mmol/l) hypoglucaemia predisposes the patient to a condition known as hypoglycaemic unawareness, which in turn means that hypoglucaemia can occur more frequently and at any time of the day, due to attenuation of the typical warning symptoms of a declining blood glucose level, e.g. hunger, perspiration etc.
Notably, the incidence of hypoglycaemia is rapidly increasing as diabetic patients seek better control of their blood glucose levels, in order to avoid hyperglycaemia. An active life, involving exercise as prescribed for diabetics, also adds to the risk of hypoglycaemia unless the patient carefully controls his/her carbohydrate intake, insulin dosage and regularly monitors their blood glucose level.
There is presently no satisfactory therapeutic regime for the prevention of nocturnal and morning hypoglycaemia. Patients suffering from diabetes are often recommended to eat a light meal before bedtime, e.g. potato chips or cereals. This results in an almost instant peak in blood glucose, followed by a more or less rapid decline during the night. In order to guarantee a sufficient blood glucose level throughout the night, the initial level must be very high, bordering to the unhealthy. When attempting this kind of crude self-medication, the patients have difficulty finding the optimal dose and mix of carbohydrates, and over-eating tends to be the result. There is currently no medication available with an appropriate kinetic profile to counteract the effect of the night-time intermediate-acting insulin.
A method of treating diabetic hypoglycaemia by administration of uncooked cornstarch is described in W095/24906. According to this application, published in September 1995, the patient is given about 0.1 to 1.0 g starch per kg body weight, preferably about 0.25 to 0.5 g per kg body weight. Different dosage formulations are suggested, including a suspension of starch in milk, sustained release tablets and a snack bar, containing a total of 30 g carbohydrates, but having about xc2xd to xc2xc of the carbohydrate in the form of uncooked cornstarch. Although containing xe2x80x9cslowxe2x80x9d carbohydrates in the form of cornstarch, this product contains considerable amounts of free sugar and fats, resulting both in an initially very high blood glucose peak, and in the intake of unnecessary calories in the form of fats and surplus carbohydrates. Further information concerning the sustained release tablets is not given, apart from a reference to well known techniques of tablet formulation.
U.S. Pat. No. 5,605,893 (Kaufman, F.) discloses a specific method of treating a diabetic patient and preventing hypoglycaemic episodes, said method consisting of administration to the patient of a therapeutic food composition comprising per serving or unit about 20-50 grams of nutrients, including
about 5-15 g of slowly absorbed complex carbohydrate, preferably cornstarch;
about 7-19 g of rapidly absorbed complex carbohydrate;
about 5-20 g of protein; and
about 3-7 g of fat,
said composition being substantially free from simple sugars.
U.S. Pat. No. 5,843,921 (Kaufman, F.) discloses a therapeutic food composition for treatment of diabetic patients and preventing hypoglycaemic episodes, comprising per serving or unit about 20-50 grams of nutrients, including
about 5-15 g of slowly absorbed complex carbohydrate, preferably cornstarch;
about 7-19 g of rapidly absorbed complex carbohydrate;
about 5-20 g of protein; and
about 3-7 g of fat;
wherein the amount of simple sugars other than fructose in said composition is less than about 3 g per unit.
U.S. Pat. No. 5,866,555 (Bell, S. J. et al.) discloses a diabetic supplement bar for the treatment or prevention of night time hypoglycaemia in a diabetic patient, made by blending simple carbohydrates, proteins, lipids, complex carbohydrates, and any additional additives, and homogenising the mixture into a food bar. Sucrose is presented as the preferred source of simple carbohydrates, whereas uncooked cornstarch is the preferred source of complex carbohydrates. The final fat concentration of the product is high, from 2 to 40% by weight. The remaining ingredients are:
about 10-60% by weight sucrose;
about 1-25% by weight protein;
about 1-60% by weight complex carbohydrate.
The high fat content of the above products accountsxe2x80x94together with the naturally slow degradation of uncooked cornstarchxe2x80x94for the delayed glucose release, as fat delays gastric emptying, thereby slowing the rate at which nutrients enter the intestines and become digested.
Another product, available on the market under the trade mark NiteBite(copyright) (Optim Nutrition Inc.) contains three sources of glucose: sucrose, protein and uncooked cornstarch. These components are digested more or less consecutively and are claimed to deliver glucose into the blood during a period of 6 hours or more.
U.S. Pat. No. 5,545,410 discloses the coating of a core of a carbohydrate in a food or pharmaceutical grade coating such as stearic acid, hydrogenated or partially hydrogenated oils, calcium stearate, stearyl alcohol, wax etc. The claims of U.S. Pat. No. 5,545,410 mention sucrose, glucose, lactose, dextrins, monosaccharides, disaccharides, oligosaccharides, and polysaccharides, as well as pregelatinized starches, raw starches, and modified starches. A limitation is however that the coated core has a particle size from 30-1000 xcexcm. The resulting product consists of individually coated particles or granulates thereof, the properties of the coating regulating the release of the core compound.
The related patent U.S. Pat. No. 5,360,614 discloses the above coated carbohydrated cores, further defining their size to the interval of 75-500 xcexcm, and the coating as providing for the release of substantially all said metabolizable carbohydrate into the digestive system for one-half to four hours after ingestion.
The prior art compositions fail to provide an entirely satisfactory solution for long term treatments when all effects and consequences are taken into account. The sucrose included in some preparations can lead to initial hyperglycaemia and may additionally contribute to caries and tooth decay. The proteins, and in particular the fat included in some of the above preparations provide unnecessary additional calories to patients, who in many cases already battle with weight problems.
The objective of the present invention is thus to accurately and reliably regulate blood glucose levels in humans and prevent dysglucaemia, in particular long term prevention of dysglucaemia. This objective can be divided in the prevention of dysglucaemia in diabetic patients, and in particular the prevention of nocturnal dysglucaemia in diabetic patients.
Another related objective is to prevent nocturnal hypoglycaemia in diabetic patients and in particular in type 1 and type 2 diabetics on insulin medication.
A further problem is how to prevent and/or treat dysglucaemia in both healthy subjects, such as athletes, and in unhealthy, such as patients undergoing surgery, chemotherapy etc, and in particular diabetic patients undergoing medical treatment.
Further, it is desirable to make available a simple and yet reliable way of improving the glycaemic control or stabilising the oscillating blood sugar levels typical for diabetic patients, and avoiding both the high and low blood sugar levels, both conditions injurious to the health, especially when occurring repeatedly or for prolonged periods of time.
It is particularly desirable to make available a method and composition giving a controlled, delayed enzymatic digestion of the starch and preferably a substantially linear glucose release curve and thus guaranteeing a pre-determined, stable and sufficient blood sugar level during at least 5 hours, preferably about 8 hours.
A practical problem encountered in pursuing the above objectives is how to make available a cornstarch composition having an agreeable taste and texture, suitable for daily consumption and life long treatment. This is not without significance, as a tasty product advances good compliance.
The present inventors have surprisingly found that the conversion of starch into sugar and in particular the enzymatic conversion of cornstarch into glucose, can be regulated or delayed in a controlled manner and adapted to the metabolism of the patient, without relying on the delaying effect of fat. Thus the blood sugar level can be held at a desired level, e.g. a level accurately adjusted to the metabolic needs of the patient, avoiding both peaks with the associated risk of hyperglycaemia, and low levels, and the corresponding risk of hypoglycaemia. Importantly, this can now be achieved without the administration of unnecessary surplus calories. Further, the present invention makes available a tasty and palatable product consisting substantially of native cornstarch.
The problems associated with the prior art products are solved, and the above objectives of the invention are achieved by a novel composition and a method comprising administering to the patient in question a starch product with minimised available surface area, such as a granulated and/or partially encapsulated starch, preferably native cornstarch. The method of treatment, the pharmaceutical composition itself and the process for its production are as disclosed in the attached claims.